Oxidation of 3-hydroxysteroids



United States Patent Ofiice 2,714,599 Patented Aug. 2, 1955 OXIDATION orB'HYDROXYSTEROIDS Gunther S. Fonken, Kalamazoo, Robert H. Levin,Kalamazoo Township, Kalamazoo County, and A Vern McIntosh, Jr.,Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., acorporation of Michigan No Drawing. Application July 16, 1952, SerialNo. 299,232

20 Claims. (Cl. 260397.45)

This invention relates to a chemical process for the production ofketosteroids and is more particularly concerned with a novel process forthe oxidation of secondaryhydroxysteroids to corresponding ketosteroidsusing an organic hypochlorite, especially an alkyl hypochlorite. Theoxidation of 3-hydroxysteroids to 3-ketosteroids is a particularlypreferred embodiment of the present invention.

It is an object of the present invention to provide a novel process forthe oxidation of secondary-hydroxysteroids to ketosteroids. Anotherobject is the provision of a process for the conversion of3-hydroxysteroids to 3-ketosteroids in high yields and with a minimum ofside reactions. Other objects will be apparent to those skilled in theart to which this invention pertains.

The ketosteroids, and in particular the 3-ketosteroids, which areproduced as products of the present invention are valuable precursors tophysiologically active steroids.30c,170L-dihYdIOXY-Z1-21Cet0XYpl6gl'l2t11e-1 1,20-dione, for example,when following the method of the present invention, can bequantitatively oxidized to l7a-hydroxy-2lacetoxypregnane-3,l1,20-trionewhich can thereafter be brominated at the 4-position and thereafterdehydrohalogenated according to methods wellknown in the art to producecortisone acetate. Since most physiologically active hormone andhormone-like steroids possess keto groups, and in particular a 3-ketogroup, a process which produces keto groups, and in particular a 3-ketogroup, in high yield without extensive manipulation and without thenecessity of carefully controlled conditions is of considerableindustrial importance. Moreover, that the process of the presentinvention can be conveniently performed at about room temperature addsto the convenience and simplicity of the process and is therefore anadded advantage. Furthermore, the fact that an excess of alkylhypochlorite is not disadvantageous, rather preferred, renders theprocess particularly valuable since it is well-known that reactionsusually proceed readily to completion and give higher yields of productwhen an excess of a reactant can be employed. Other advantages and useswill be apparent to those skilled in the art to which this inventionpertains.

The preferred 'secondary-hydroxysteroids used as starting compounds inthe method of the present invention are 3-hydroxysteroids which aresaturated (i. e., carbon to carbon double and triple-bonds are notpresent), and which do not have unsubstituted primary orsecondaryhydroxy groups other than the 3-hydroxy group since theseunsaturated linkages and hydroxy groups, which also usually react withalkyl hypochlorites, sometimes unduly complicate the reaction. Steroidsof the above type, but containing, in addition, an 111::(01' B)-hydroxygroup, are also included as preferred starting compounds since thellu-hydroxy group is substantially non-reactive with hypochlorites, andthe 11,6-hydroxyl group is smoothly converted to an ll-keto group byusing an additional quantity of the alkyl hypochlorite. This delineationof preferred starting compounds, however, is not to be construed aslimiting the scope of this invention, as numer- (ill ous othersecondary-hydroxysteroids are converted to ketosteroids by the processof this invention and are also included as starting materials within thescope of this invention. If additional groups such as, for example,unsaturated linkages or other hydroxy groups, or other groupings, arepresent which are reactive with the alkyl hypochlorite under theconditions of the reaction, an additional amount of the alkylhydrochlorite may be included in the reaction mixture to react withthese additional groups. Alternatively these additional reactive groupsin the starting compounds may be protected and later regenerated in theproduct obtained by the process of the present invention, for example,carbon to carbon double-bonds may be protected by adding two bromineatoms and later regenerated by treating with zinc. Additional hydroxygroups may be protected, for example,

by selective ester or ether formation and later regenerated byhydrolysis.

Of the preferred starting steroids, steroids of particular interest arethose having the following structural formula:

CHa

wherein R is oz-hYdIOXY or p-hydroxy; R1 is hydrogen, a-hydroxy or anacyloxy ester thereof such as, for example, formyloxy, acetoxy,benzoyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy,phenylacetoxy, octanoyloxy, or the like, especially lower alkanoyloxy,or fl-hydroxy, or ketonic oxygen; R2 is hydrogen or hydroxy; and R3 isacetyl, acyloxyacetyl, e. g., acetoxyacetyl propionoxyacetyl,butyryloxyacetyl, octanoyloxyacetyl, benzoyloxyacetyl, or the like,especially acyloxyacetyl wherein the acyloxy group is alower-alkanoyloxy group, or haloacetyl, e. g., bromoacetyl,chloroacetyl, or the like.

According to the method of the present invention, asecondary-hydroxysteroid, preferably a 3-hydroxysteroid is contactedunder substantially anhydrous conditions, with an organic hypochlorite,preferably with an alkyl hypochlorite.

In carrying out the process of the present invention, asecondary-hydroxysteroid, preferably a 3-hydroxysteroid is contacted,under substantially anhydrous conditions,

with an alkyl hypochlorite. The reaction is usually conducted in thepresence of a solvent such as, for example, tertiary-butyl alcohol,tertiary-amyl alcohol, chloroform, or the like, the concept, definition,and use of a solvent being well-known in the art. The temperatureemployed is usually between about minus twenty and about plus fiftydegrees centigrade, ordinarily at about room temperature, e. g., betweenabout twenty and about thirty degrees centigrade, for a reaction periodof between about ten minutes and about twenty-four hours, the exactreaction period required for complete reaction being in part dependentupon the reaction temperature and the alkyl hypochlorite employed andthe molar ratio thereof to starting steroid, as well as other factorsapparent to one skilled in the art. The amount of water present in thereaction mixture should be less than 0.5 per cent by weight andpreferably less than 0.1 per cent by weight.

Although the use of organic hypochlorites generally is within thepurview of the present invention, alkyl hypochlorites are usually used.The secondary-alkyl hypochlorites are relatively unstable and for thisreason are not the preferred hypochlorites. Since methyl hypochlorite isvery unstable and even explosive at room temperature, it is preferablynot employed in carrying out the process of the present invention.Tertiary-alkyl hypochlorites are very desirable oxidizing agents whenfollowing the method of the present invention and, of these,tertiarybutyl hypochlorite has been found to be particularlysatisfactory, being quite stable and enabling frequent procurement ofpractically quantitative yields of the desired ketosteroid.Tertiary-butyl hypochlorite is therefore a preferred alkyl hypochlorite.

The amount of alkyl hypochlorite used 1s generally between about one andabout five moles, or more, per mole of steroid in order to convert asecondary-hydroxy group to a keto group in the process of thisinvention. Best yields appear to be obtained when the alkyl hypochloriteis employed in a molar ratio to starting secondary-hydroxysteroid ofabout two to one and preferably trom about three to about four moles ofalkyl hypochlorite to one mole of starting steroid since the large molarexcess appears to enhance the yield of product. However, if anadditional group which reacts with the alkyl hypochlorite is present,the amount of alkyl hypochlorite used should be at least about one moleplus the amount required to react with the additional group, preferablybetween about three and about four times this combined amount, permoleof starting steroid. I

If desired, the reaction may be performed in the presence of anacid-binding agent, for example, a base such as pyridine, or otheracid-binding agent, which is essentially non-reactive with the alkylhypochlorite, the starting steroid, and the steroid product. Inconverting a secondary-hydroxy group to a keto group, for example, aboutone mole of the acid-binding agent pyridine is used per mole of startingsteroid. However, the inclusion of an acid-binding agent is usuallyunnecessary to obtain high yields of desired product. In some instancesthe amount of excess alkyl hypochlorite used may be reduced without lossin yield if an acid-binding agent is included.

While considerably broader ranges of reaction temperature, e. g.,between about minus twenty and about plus fifty degrees centigrade, areincluded within the scope of the present invention, the preferredreaction temperature is room temperature, e. g., between about twentyand about thirty degrees centigrade, as high yields of desired productare obtained within this temperature range and external cooling orheating is usually unnecessary. Sometimes, however, a reactiontemperature slightly below room temperature will enhance the yield ofdesired product when the oxidation of a particular startingsecondaryhydroxysteroid is unduly accompanied by side reactions.

Usually reaction temperatures substantially above room temperature arenot preferred. In general, the preferred reaction temperature, whileusually room temperature,

varies somewhat with the starting steroid and the alkyl I hypochloriteemployed. Temperatures substantially below minus twenty andsubstantially above plus fifty degrees centigrade are operative incertain instances. it Ot-ChlO- rination of a keto group is a significantside reaction, it is usually preferred to conduct the reaction in theabsence of light in order to obtain maximum yields of the unchlorinatedketosteroid. If, instead, it is desired to obtain cit-chlorination, thereaction may be conducted in the presence of light and in some instancesillumination may be preferred.

Tertiary alkanols have been found to be excellent reaction solvents andanhydrous tertiary-butyl alcohol, a preferred solvent, has been usedwith repeated success. Other solvents such as, for example,tertiary-amyl alcohol, chloroform, ethylene dichloride, pentane, hexane,and the like,

are also suitable. The choice of reaction solvent depends in part on thesolubility of the starting steroid in the solvent.

The progress of the oxidation can conveniently be followed by iodometrictitration, according to methods known in the art, of aliquot samplestaken from time to time from the reaction mixture. When consumption ofalkyl hypochlorite has essentially ceased or when the theoretical amounthas been consumed, the reaction is usually complete and further reactiontime is unnecessary.

Isolation of the product of the present invention is convenientlyachieved, for example, by distilling the volatile components of thereaction mixture at reduced pressure and, if an acid-binding agent isused, washing the residue with water. The resulting residue consists ofa very high, and frequently quantitative, yield 0g ketosteroid in a highstate of purity. If a significant amount of correspondinga-chloroketosteroid is present and it is desired to obtain pureunchlorinated product, a simple purification comprises dissolving thisresidue in acetic acid and treating the solution with zinc dust whichremoves this chlorine thereby purifying the desired ketosteroid.Alternatively, the residue can be crystallized from an organic solventaccording to methods well-known in the art.

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

FREPARATION 1.3 0t,170t-DIHYDROXYPREGNANE-1 1,20-

nroun 20-ETHYLENE GLYooL KETAL A mixture of 260 milligrams of3m,17o-dihydroxypregnane-11,20-dione [Kritchevsky, Garmaise, andGallagher, J. Am. Chem. Soc., 74, 483 (1952)], five milliliters ofethylene glycol, fifty milligrams of para-toluenesulfonic acidmonohydrate and 100 milliliters of benzene was placed in a reactionflask which was equipped with a reflux condenser and a water trap soarranged that the condensed vapors passed through the water trap beforereturning to the reaction flask. The mixture was heated to reflux andwas allowed to reflux for five hours while at the same time beingagitated. The water which formed was removed by co-distillation withbenzene and was collected in the water trap. The reaction mixture wascooled and poured into a dilute solution of sodium bicarbonate. Thebenzene layer was separated, washed with water, dried and concentratedto dryness. The residue was chromatographed over forty grams of Florisilmagnesium silicate using eighty-milliliter portions of a mixture ofethylene dichloride with successively greater proportions of acetone forelution. The material, which was eluted with ethylene dichloride-acetone(12:1 and 8:1), weighed 141 milligrams after removal of the solvents.Recrystallization from benzene-Skelly Solve 23 gave fifty milligrams of3a,l7ct-dihydroxypregnanc- 11,20-dione ZO-ethylene glycol ketal meltingat 144 to 146 degrees centigrade.

Analysis:

Calculated for CzsHssOs C, 70.37; H, 9.25 Found C, 70.65; H, 9.28

PREPARATION 2.-30t,111x,17oc-TRIHYDROXYPREGNAN-20 our: AND30L,1113,170-TRIHYDOXPR-EGNAN-ZO-ONE To a solution of two grams oflithium aluminum hydride in 200 milliliters of anhydrous ether was addeddropwise, with stirring, two grams of3a,17et-dihydroxypregnane-ll,20-dionc 2G-cthylcne glycol ketal fromPreparation 1 in twenty milliliters of anhydrous benzene. The mixturethen was stirred at room temperature for one hour followed by boilingunder reflux for an additional hour. With continued stirring theresulting mixture was cooled and treated cautiously with water addeddropwise. The resulting solution containing the3a,11,l7m-trihydroxypregnan-ZO-one 20-ethylene glycol ketals then wasadmixed with a ten-fold excess of dilute hydrochloric acid and theresulting heterogeneous mixture was stirred vigorously for twenty hoursat room temperature. The product was isolated by separating the organicand aqueous layers, extracting the aqueous layer with ether, combiningthe ether extract with the organic layer, washing the organic solutiontwice with water, drying the washed solution over anhydrous sodiumSulfate, removing the drying agent by filtration, removing was obtainedfrom the remaining mother liquor by dis- 1 tillation of the solventsunder reduced pressure, redis solving the residual oil in a minimumamount of ethyl acetate, and diluting with Skelly Solve B.

Crop A was recrystallized twice from a mixture of ethyl acetate andSkelly Solve B and once from a mixture of acetone and Skelly Solve B togive 240 milligrams of 3a,11a,17a-trihydroxypregnan-20-one as needles;melting point 184-186 degrees centigrade; plus 52 degrees in acetone.

Analysis: 1

Calculated for C21H3404 C, 71.9; H, 9.71 Found C, 72.2; H, 9.53

Crop B was recrystallized once from a mixture of ethyl acetate andSkelly Solve B and once from a mixture of acetone and Skelly Solve B togive 275 milligrams of 3a,11,8,17a-trihydroxypregnan-ZO-one as plates;melting point 213-216 degrees centigrade; [M plus 73 degrees in acetone.

Analysis:

Calculated for C21H3404 C, 71.9; H, 9.71 Found C, 72.1; H, 9.81

PREPARATION 3.-3,B-AcEToxYPREoNANE-1 1,20-DIONE3,8-hydroxypregnane-11,20-dione [Von Euw, Lardon, and Reichstein, Helv.Chim. Acta, 27, 821 (1944)], 8.18 grams, was dissolved in a mixture offifty milliliters of acetic anhydride and two milliliters of pyridine,and the resulting solution was allowed to stand at room temperature for24 hours. The mixture was then poured into 325 milliliters of Water andallowed to stand at room temperature for several hours to permitdecomposition of the excess acetic anhydride. The solid product wasremoved by filtration and dried recrystallizations from aqueous acetonegave 2.75 grams, melting point 155-162 degrees centigrade. Repeatedrecrystallization from aqueous acetone gave3,6-acetoxypregnane-11,20-dione; melting point 164165 degreescentigrade; M1 plus 99 degrees in chloroform. Analysis:

Calculated for C23H34O4 C, 73.90; H, 9.10 Found C, 73.69; H, 9.02

PREPARATION 4.3 ,6, 1 1, 2O-TRIAcEToxY-9( 1 1), 17(20)- PREGNADIENE Amixture of 2.75 grams of 3B-acetoxypregnane-1l,20- dione fromPreparation 3, 0.73 gram of para-toluenesulfonic acid monohydrate, andninety milliliters of acetic anhydride was heated to boiling and allowedto distil slowly for three hours, 71 milliliters of distillate beingcollected. Another fifteen milliliters of distillate was col lected bydistillation under reduced pressure, and the resulting residue wascooled, diluted with 85 milliliters of ether, washed with one per centaqueous sodium bicarbonate solution and with water, and dried overanhydrous sodium sulfate. After removing the drying :agent byfiltration, the ether was removed by distillation giving 3.5 grams of3,6,1l,20-triacetoxy9(l1),17(20)- pregnadiene as a glass.

PREPARATION 5. 17(20)-oxIno-3,6,1 1,20-rRIAcEToxY- 1 9(1 1)-PREGNENE3,8,11,20 triacetoxy 9(11), 17 pregnadiene, 3.5

under vacuum. Two

grams, from Preparation 4 was dissolved in seventeen milliliters ofchloroform and the resulting solution cooled to a temperature of zero tofive degrees centigrade. A mixture of 170 milligrams of anhydrous sodiumacetate and 7.7 milliliters of 38 per cent peracetic acid was added withstirring, the temperature of the reaction mixture being maintained atzero to five degrees centigrade. The resulting mixture was stirred atthis temperature for ten minutes, then allowed to come to roomtemperature, and stirred for an additional ninety minutes. The mixturethen was diluted with eighty milliliters of ether, washed with fourfifteen-milliliter portions of five per cent aqueous sodium hydroxidesolution, and three fifteen-milliliter portions of Water, and dried overanhydrous sodium sulfate. Removal of the drying agent by filtration anddistillation of the solvents under reduced pressure gave 3.5 grams of17(20) oxido 33,11,20 triacetoxy 9,(11) pregnene as a viscous oil.

PREPARATION 6-35, 1 7a-DIHYDROXYPREGNANE-1 1,20-

DIONE PREPARATION 7 .3 p, 17 oc-DIHYDROXYPREGNANE-l 1,20- DIONEZO-ETHYLENE GLYcoL KETAL In the same manner as given in Preparation 1,36,17- dihydroxypregnane-l1,20-dione ZO-ethylene glycol ketal isprepared from 3B,17e-dihydroxypregnane-1l,20-dione from Preparation 6 byreaction with ethylene glycol in the presence of para-toluene-sulfonicacid.

PREPARATION 8.3,8, 1 1a,17oc-TRIHYDROXYPREGNAN-20- ONE AND243,11,8,l7a-TRIHYDROXYPREGNANQO-ONE One gram of3,8,l7a-dihydroxypregnane-11,20-dione ZO-ethylene glycol ketal fromPreparation 7 was dissolved in fifteen milliliters of benzene, reducedwith one gram of lithium aluminum hydride in milliliters of ether, andsubsequently hydrolyzed with acid using the procedure of Preparation 2.The ratio was about. three parts of 35,11n,17a-tIihydrOXypregnan-ZO-oneto about five parts of 3,8,1 113,17a-trihydroxypregnan-20-one.

Analysis of 3,8,11a,17a-trihydroXypregnan-ZO-One:

Calculated for Cal-13404 C, 71.9; H, 9.71 Found: C, 71.8; H, 9.82

Analysis of 3,8,11B,l7a-trihydroxypregnan-20-one:

Calculated for C21H24O4 C, 71.9; H, Found C, 72.0; H,

PREPARATION 9.-1 lzx-HYDROXYPROGESTERONE A medium was prepared from fivemilliliters of corn steep liquor, twenty grams of Edamine commerciallactalbumin digest, and fifty milligrams of Cerelose commercialdextrose, per liter of tap water and adjusted to a pH of between about5.5 and about 5.9. To four liters of this medium containing a 32 to 48hour growth, at room temperature with aeration, of Rhizopus arrhizus,was added one gram of progesterone in fifty milliliters of acetone. Theculture was then incubated at room temperature for 48 hours. At the endof this time the pH of the medium was 3.5 and the fermentation liquorand mycelia were extracted successively with three one-liter portions,one twoliter portion, and one one-liter portion of methylene chloride.The methylene chloride extracts were combined and washed with two400-milliliter portions of two per cent aqueous sodium bicarbonatesolution and three SOD-milliliter portions of Water. The methylenechloride extract was evaporated to dryness in vacuo and the solids takenup in fifty milliliters of methylene chloride. The solution wastransferred to a 100-milliliter beaker and evaporated by a stream ofair. The solids, weighing 1.585 grams, were dissolved in fivemilliliters of hot methanol and allowed to cool slowly at roomtemperature, whereupon 75 milligrams of crystals separated ou The motherliquor was freed of solvent by aeration, dissolved in fifty millilitersof benzene and chromatographed over alumina (A1203). Fifty grams ofacid-washed alumina, dried at 45 degrees centigrade, was used asadsorbent and 100- I milliliter portions of solvents were used todevelop the column. The solvents and the order used were as follows:benzene, benzene, benzene plus per cent ether, benzene plus 5 per centether, benzene plus per cent ether, benzene plus 10 per cent ether,benzene plus 10 per cent ether, benzene plus 50 per cent ether, benzeneplus 50 per cent ether, ether, ether, ether plus 5 per cent chloroform,ether plus 5 per cent chloroform, ether plus 10 per cent chloroform,ether plus 10 per cent chloroform, ether plus 50 per cent chloroform,ether plus 50 per cent chloroform, chloroform, chloroform, chloroformplus 5 per cent acetone, chloroform plus 5 per cent acetone, chloroformplus 10 per cent acetone, chloroform plus 10 per cent acetone,chloroform plus 50 per cent acetone,

chloroform plus 50 per cent acetone, acetone, acetone,

acetone plus 5 per cent methanol, acetone plus 5 per cent methanol,acetone plus 10 per cent methanol, acetone plus 10 per cent methanol,acetone plus 50 per cent methanol, acetone plus 50 per cent methanol.The chloroform and chloroform plus five per cent acetone eluates werecombined, evaporated to dryness, and the residue dissolved in twomilliliters of hot methanol and filtered. After overnight refrigeration,171 milligrams of crystalline llot-hydroxyprogesterone, melting at 166to 167 degrees centigrade, was obtained. A sample recrystallized frommethanol gave the following constants: melting point, 16-167 degreescentigrade; [111 plus 175.9 degrees (chloroform).

Analysis:

Calculated for C21H3003 C, 76.4; H, 9.10 Found C, 76.6; H, 8.92

The structure of this product was further established by its conversion,with chromic acid in acetic acid, to ll-ketoprogesterone fReichstein,Helv. Chim. Acta 23. 684 (1940); ibid. 26, 721 (1943)].

PREPARATION 1().-11a-HYDROXYPREGNANE-3,20-D1ONE A solution of 250milligrams of lla-hydroxyprogesterone from Preparation 9 in 100milliliters of ethanol i containing six drops of triethylamine wassubjected to hydrogenation at room temperature under a pressure of aboutten pounds of hydrogen in the presence of milligrams of a thirty percent palladium-charcoal catalyst in a Parr apparatus with an auxiliarymercury manometer. The time required for the hydrogenation was abouttwenty minutes. The reaction mixture was filtered and the solvent wasevaporated to yield 265 milligrams of material melting at 145-185degrees centigrade. This product was extracted with a mixture of onemilliliter of ether and nine milliliters of Skelly Solve B. On standing,the extract deposited eighty milligrams (32 per cent) of11ahydroxypregnane-3,20-dione as feathery needles which melted at -90degrees centigrade. Recrystallization from a mixture of about six dropsof ethyl acetate and five milliliters of Skelly Solve B did not changethe melting point.

Analysis:

Calculated for C21H3203 C, 75.86; H, 9.70 Found C,76.13; H, 9.73

PREPARATION 1 1 .3 01,1 ltx-DHIYDROXYPREGNAN-ZO-ONE To a solution of5.31 grams of llot-hydroxypregnane- 3,20-dione of Preparation 10 inmilliliters of peroxide-free dioxane maintained at fifty degreescentigrade in PREPARATION 12.-1 1a-ACETOXYPREGNANE-3 ,20-DI0NE A mixtureof 70.5 milligrams of llu-hydroxypregnane- 3,20-dione from Preparation10, 0.8 milliliter of acetic anhydride, and 0.7 milliliter of pyridinewas allowed to stand for sixteen hours at room temperature and thenpoured into ice water. The precipitated product was isolated byfiltration and dried. The yield of llot-acetoxypregnane-3,20-dione,melting at 1435-1465 degrees centigrade, was 67 milligrams (84 percent). After one recrystallization from ether-Skelly Solve B, themelting point was -151 degrees centigrade; [a] =plus 63 degrees (c:0.803in chloroform).

Analysis:

Calculated for C2sHa4O4 C, 73.76; H, 9.15 Found C, 73.93; H, 9.32

In the same manner other l1u-acyloxypregnane-3,20- diones are preparedfrom 1la-hydroxypregnane-3,20- dione, including 11cc formyloxypregnane3,20 dione (using formic acid as the acylating agent);lloc-propionoxypregnane-3,20-dione; 11a-butyryloxypregnane-3,20- dione;11oz-octanoyloxypregnane-3,ZO-dione; and the like.

PREPARATION 13 .-3 oz, 1 1a,20-TRIAcEToxY-17 (20) PREGNENE Four hundredand five (405) milligrams of 3a,11adihydroxypregnan-ZO-one fromPreparation 11, 200 milligrams of para-toluene-sulfonic acid monohydrateand seventy milliliters of acetic anhydride were heated to distillationtemperature and allowed to distil slowly for three and one-half hours. Atotal of sixty milliliters of distillate was collected. The residue wascooled to room temperature, poured into ice-water, and the resultingcrystalline product collected and washed with water. Recrystallizationfrom acetone-water yielded 332 milligrams of3a,11a,20-triacetoxy-17(20)-pregnene, melting at 200-203 degreescentigrade.

PREPARATION 14.3 51 1a,20-TRrAcEToxY-17 (20- PREGNENE Using theprocedure described in Preparation 13, 3(3-hydroxy-l1a-acetoxypregnan20-one (prepared by the reduction of the1lot-acetoxypregnane-3,20-dione of Preparation 12 with hydrogen at twoto three atmospheres pressure in methanol at room temperature using aRaney nickel catalyst), is converted to 3B,11a,20' triacetoxy-17(20)-pregnene with acetic anhydride in the presence ofpara-toluenesulfonic acid.

In the same manner as given above in Preparation 13 and Preparation 14,other 3oc(Ol. /3),l1ot,20-triacyloxyl7(20)-pregnenes are prepared,including 3u,11a,20-tripIopionoxy-l7(20)-pregnene; 319,1lot,20-tripropionoxy-17- (20)-pregnene; 33,20-diacetoxy 111xformyloxy-17(20)- pregnene, 35,20dipropionoxy-l1a-acetoxy-l7(20)-pregnene;3a,l1a,20-trioctanoyloxy-17(20)-pregnene; 3fi,20-dioctanoyloxy-llat-propionoxy-l7(20)-pregnene; 3a,1 1a,20- tributyryloxy 17(20)pregnene; 3a,11a,20 trivaleroyloxy-17(20)-pregnene; 3a,11oc,20trihexanoyloxy 17(20)- pregnene; 3a,11a,20 triheptanoyloxy 17(20)pregnene; and 3 oz, 1 1a,20-trioctanoy1oxy-17(20)-pregnene.

PREPARATION 15.-17(20)-OXIDO-3oc,11a,20-

TRIACETOXYPREGNANE One and one-half grams of 3a,11u,20-triacetoxy17(20)-pregnene (Preparation 13) was dissolved in 7.5

milliliters of chloroform, and the solution was cooled in an ice bath toabout five degrees centigrade. Three and three-tenths milliliters ofccrnmercial grade forty per cent peracetic acid solution in which 100milligrams of sodium acetate had been dissolved was added, and theresulting mixture was then shaken on a mechanical shaking machine forabout two hours at room temperature to complete the reaction. Themixture containing the crude product was diluted with fifty millilitersof methylene chloride and then washed with several 25-milliliterportions of ice-cold five per cent aqueous sodium hydroxide solutionfollowed by 25-milliliter portions of water until the wash solution wasneutral to pH test paper. The neutral solution was dried with anhydroussodium sulfate and then filtered to remove the drying agent. The whitecrystalline residue obtained on evaporating the solvent from the clear,dry solution melted at 210-2l3 degrees centigrade. Recrystallizationfrom a mixture of ethyl acetate and Skelly Solve B gave ilufiy needlesof 17(20)-oxido-3 x,11a,20-triacetoxypregnane, melting at 214-217degrees centigrade.

Analysis: Calculated for C2'zH4oO'1 C, 68.04; H, 8.46 Found C, 68.33; H,8.62

PREPARATION 16.17(20)0XIDO-3B,11ot,20- TRIACETOXYPREGNANE Using theprocedure described in Preparation 15, 3B,l1a,20-triacetoxy-l7(20)pregnene from Preparation 14 is converted to17(20)-oxido-3fi,l1a,20-triacetoxypregnane by oxidation with peraceticacid in the presence of sodium acetate.

In the same manner as given above in Preparation 15 and Preparation 16,other l7(20)-oxido-3ot(orfi),11a,20- triacyloxypregnanes are preparedfrom the corresponding 3a(or [8),1lat,20-triacyloxy-l7(20)-pregnenes,including 17 (20 -oxido-3 a,l la,20-tripropionoxypregnane; 17 (20)oxide-3B,] 1a,20-trlpropionoxypregnane; 11a-acetoxy-3fi,20-dipropiOnOxy-17 20) -oxidopregnane; l lot-formyloxy-3B,20-diacetoxy-17(20)-oxidopregnane; 17(20) oxidO- 301,11a,20-trioctanoyloxypregnane; 3 3,20-dioctanoyloxyl7(20)-oxido-llapropionoxypregnane; 17(20) oxido- 301,11a,20-tributyryloxypregnane;17(20) oxido-3a,llot, 20-trivaleryloxypregnane;17(20)-0xido-3a,11,20-trihexanoyloxypregnane; 17(20)oxide-311,11a,20-triheptanoyloxypregnane; 17(20) oxido3a,11u,20-trioctanoyloxypregnane; and the like.

PREPARATION 17 .-1 1a AcBrOxY-3 :,17oz-DIHYDROXYPREG- NAN-ZO-ONE AND30,l ,l7a-TR1HYDROXYPREGNAN-2O- ONE Nine hundred milligrams of17(20)-oxido-3ot,l1a,20 triacetoxypregnane (Preparation was dissolved infifty milliliters of alcohol, and to the resulting solution was addedwith swirling 11.3 milliliters of a 0.5 normal aqueous sodium hydroxidesolution. After standing at room temperature for thirty minutes, thesolution was extracted with chloroform, and the chloroform extract wasthen washed with twenty per cent aqueous sodium chloride solution anddried with anhydrous sodium sulfate. The drying agent was removed byfiltration, and the solvent was removed by evaporation under reducedpressure giving the product as a colorless, viscous oil. The oil wasdissolved in 100 milliliters of benzene, and the solution was passedthrough a chromatographic column packed with ninety grams of Florisilmagnesium silicate to adsorb the product. The product was eluted fromthe column by washing with the following solvent mixtures in succession:Ten 100-milliliter portions of 5 per cent acetone and 95 per cent SkellySolve B, ten 100- milliliter portions of 10 per cent acetone and 90 percent Skelly Solve B, and then 100-milliliter portions of per centacetone and 80 per cent Skelly Solve B. On evaporation of the solventsfrom the various fractions,

lif the product had been separated into two parts, both colorlessviscous oils. The product from the first fractions wasllot-acetOxy-3a,17rr-dihydrOXypregnan-ZO-One, as confirmed by analyticaldata, and the product from the later fractions was30,llot,l7a-trihydrOXypregnan-ZO- .One, identical with the30,11a,l7a-trihydroxypregnan-20- one obtained in Preparation 2. Theratio was about one part of the acetoxy compound for every nine parts ofthe trihydroxy compound.

Analysis of 11ot-acetoxy-3u,l7a-dihydroxypregnan-20- one:

Calculated for C23H3s05 C, 70.37; H, 9.25

Found C, 70.30; H, 9.30

PREPARATION 18.-1 10L-ACETOXY-3,B,170t DIHYDROXYPREG- NAN-ZO-ONE AND 3,3, 1 1a,17tx-TRIHYDROXYPREGNAN-20- ONE Using the procedure described inPreparation 17, an alcohol solution of17(20)-oxido-3fl,llot,20-triacetoxypregnane (Preparation 16) wasconverted by treatment with an aqueous sodium hydroxide solution to anoily product which was separated into11a-acetoxy-3fl,17a-dihydroxypregnan-ZO-one and3,8,l1ot,17a.-trihydroxypregnan-ZO-one, as confirmed by analytical data.The ratio was about one part of the acetoxy compound for every ten partsof the trihydroxy compound.

Analysis of 1lot-acetoxy-3B,17ct-dihydroxypregnan-20- one: Calculatedfor CzsHssOs C, 70.37; H, 9.25 Found C, 70.43; H, 9.19 Analysis of35,1111,17a-trihydroxypregnan-20-one:

Calculated for Carl-13404. C, 71.96; H, 9.78 Found C, 71.80; H, 9.82

PREPARATION l9.-21-BI .oMo-3 04,1 10:, l 7ct-TRIHYDROXY- PREGNAN-ZO-ONE3a,l1a,17atrihydroxypregnan-20-one (Preparation 2 or 17), dissolved inchloroform, is treated with a solution of bromine in chloroform at aboutforty degrees centigrade. After completion of the bromination, thechloroform is distilled to give a theoretical yield of 2l-bromo-3a,1la,17ot trihydroxypregnan 20 one; melting point 122.5 to 127 degreescentigrade.

PREPARATION 20.21-BROMO-3a,1 1fi,17zx-TRIHYDROXY- PREGNAN-ZO-ONE 3ot,113,l7u-trihydroxypregnan-20-one (Preparation 2), brominated as inPreparation 19 yields 2l-bromo-3u,l1fi, 17a-trihydroxypregnan-20-one inquantitative yield.

PREPARATION 21 .-2 1 ammo-35,1 1a, 1 7ot--TRIHYDROXY- PREGNAN-ZO-ONEBromination of 3,8,11a,17u-tIihydrOXypregnan-ZO-one (Preparation 8 or18) using the procedure of Preparation 19 gives2l-bromo-3fi,lla,l7wtrihydrOXypregnan-ZO-one in high yield.

PREPARATION 22.-2l-BRoMO-3 5,1 1 e, 17 ot-TRIHYDROXY- PREGNAN-20-0NETreatment of $8,115,170; trihydroxypregnan 20 one (Preparation 8) withbromine in chloroform, according to the procedure of Preparation 19yields 21-brorno3B,1l,B, 17ot-trihydroxypregnan-20-one.

PREPARATION 23.-21-BR0Mo-1 c-ACETOXY-3 oz,170l. DIHY-DROXYPREGNAN-ZO-QNE 11a-acetoxy-3a,17u-dihydroxypregnan-20 one(Preparation 17) brominated by the method of Preparation 19 gives aquantitative yield of 21-bromo-11a-acetoxy-3a,17a-dihydroXypregnan-20-one.

In the same mannerother 21-bromo-11a-acyloxy-3a,17a-dihydrOXypIegnan-ZO-ones are prepared from corresponding 11a acyloxy3a,17a-clihydroxypregnan-20- ones, including21-bromo-11a-formyloxy-3a,17a-dihydroxypregnan--one; 2l-bromo-1lu-propienoxy-3a,l7otdihydroxypregnan-ZO-one; 2 l -bromo-l1u-butyryloXy-3 a, 17ot-dihydroxypregnan-20-one; 21-bromo-1la-valeryloxy- 3a,17ot-dihydroxypregnan-20-one; 21 bromo 11ahexanoyloxy-Sa,17a-dihydroXypregnan-20 one; 21 bromolla-heptanoyloxy30,l70c dihydroxypregnan 20 one; 2l-bromo-llu-octanoyloxy 3o ,17adihydroxypregnan- 20-one; and the like.

PREPARATION 24.2 l-BROMO- 1 oc-ACETOXY-3 p, 17 a-DII-IYDROXYPREGNAN-20-0NE PREPARATION .--2 1 -CHLORO-3 y.,1 lot, 1 7cl-TRIHYDROXY- PREGNAN-ZO-ONE A solution of3oc,110c,l7oz-tIihYdI'OXYpI'GgIlaH-ZO-01'1B (Preparation 2 or 17) incarbon tetrachloride is treated with chlorine, dissolved in carbontetrachloride, at about room temperature. Distillation of the carbontetrachloride solvent gives21-chloro-3a,1la,l7a-trihydroxypregnan-ZO-one in excellent yield.

In the same manner other 21-chloro-3,17a-dihydroxy-11-oxygenatedpregnan-ZO-ones are obtained from corresponding3,17a-dihydroxy-1 1-oxygenatedpregnan-20-ones,

including 21 chloro 3a,ll,8,17u trihydroxypregnan- 20 one; 21 chloro3fl,1loc,l7oc trihydroxypregnan- 20-one; 21-chloro-3B,115,17a-trihydroxypregnan-ZO-one; 21 chloro 11oz aeetoxy 3a,17 xdihydroxypregnan- 20-one; 2 1-ch1oro-1 1 Ot'PI'OPiOl'lOXY-S on, 17u-dihydroxypre gnan-20-one;21-(21'11010-1la-btllZYrYlOXY-30:,17oc-dihYdIOXY- pregnan-ZO-one;21-chloro- 1 lwva1eryloXy-3 a, 1 7u-dihy droXypregnan-20-one;21-chloro-1 1wheXanoy1oxy-3oc, 17adihydroxypregnan-ZO-one;2l-ch1oro-llot-heptanoyloxy- 3a,l7a-dihydroxypregnan-ZO-one; 2l-chloro-11u-octanoyloxy-3a,17a-dihydroxypregnan-20-one;ZI-ChlOIO-llaformyloXy-3fi, 17 a-dihydroxypregnan-ZO-one; 21 -chlorol1a-acetoxy-3fl,17a-dihyclroxypregnan-20-one; 2l-chloro- 11a propionoxy3,6,17oc dihydroxypregnan 20 one; 21 chloro 11a butyryloxy 313,170:dihydroxypreg nan-20-one; 21-chloro-1l0L-V2ll61YlOXy-3fi,17a-d1hYdI'OXypregnan-ZO-one; 2 l-chloro-l1OL-h6X31'10ylOXy-3 ,B,17a-dihydroxypregnan 20 one; 21 chloro llocheptanoylorry-3p,170-dihydroxypregnan-ZO-one; 21-chloro-1 lot-OC-tanoyloxy-3B,17a-dihydroxypregnan-ZO-one; and the like.

PREPARATIoN 26.--21-AcEToxY-3 00,1 la,17ot-TRIHYDROXY PREGNAN-ZO-oNE21-bromo-3a,11a,l7wtrihydroxypregnan-20-one (Preparation 19), dissolvedin acetone is heated for about sixteen hours under reflux with excessanhydrous potassium acetate in the presence of a trace of potassiumiodide and a trace of acetic acid. The resulting solution is cooled andthen diluted with water to precipitate the2l-acetoXy-3a,11a,17a-trihydroxypregnan-ZO-one; melting point 185 to 189degrees centigrade. The yield is nearly quantitative.

In the same manner other21-aCylOXy-3oc,1104,17a-t1ihydroxypreguan-ZO-ones are prepared from21-bromo-3a,- 11a,17a-trihydroxypregnan-20-one, and the appropriatepotassium acylate, including2l-forrnyloXy-3ot,11u,17atrihydroxypregnan-ZO-one; 2l-p1'OP10I1OXy-3oc,11a,17u-trihydroXypregnan-20-one; 21-butyryloXy-3u,1loc,17oc-llfihydroxypregnan 20 one; 21 valeryloxy3a,lloc,l7oztrihydroxypregnan-ZO-one; 21-hexanoyloxy-3ot,l 100,170:-trihydroxypregnan-ZO-one; 21-heptanoyloxy-3 or, 1 111,179;-trihydroxypregnan-20-one; 21-octanoyloxy-3ot,110:,l7oc-trihydroxypregnan-20-one; and the like.

PREPARATION 27.-21-AcEToxY-3 a,l 113,17u-TRIHYDR0XY- PREGNAN-20-0NEReplacement of the bromine atom in 21-bromo-3 11,115,-17a-trihydroxypregnan-20-one (Preparation 20) by an acetoxy group isaccomplished in the same manner as in Preparation 26. The yield of21-acetoxy-3a,1lfi,l7a-trihydroxypregnan-ZO-one is the theoreticalamount.

In the same manner other2l-acyloxy-3u,l1,8,17u-trihydroxypregnan-ZO-ones are prepared from21-bromo- 30,l1,6,17a-trihydroxypregnan-ZO-one and the appropriatepotassium acylate, including 21-formyloxy-3a,l1,8,17utrihydroxypregnan-20-one; 21-propionoxy-3u,1 18,17a-trihydroxypregnan-20-one; 21-butyryl0xy-3a,l 10c, i7or-tIihY-droxypregnan 20 one; 21 valeryloxy 3a,11fl,l7octrihydroxypregnan-20-one;21-hexanoyloxy-3 0:,1 15,17 trihydroxypregnan-20-one;21-heptanoyloXy-3a,1 118,17- trihydrOXypregnan-ZO-one;21-octanoy1oxy-3a,11B,17x-trihydroxypregnan-ZO-one; and the like.

PREPARATION 28 .-2 1-AcEToxY-3 [3,1 1 a, 17 u-TRIHYDRO XY-PREGNAN-ZO-ONE 21-bromo-3fl, l 1a,17a-trihydroxypregnan-20-one(Preparation 21) is converted to21-acetoxy-3;3,11a,17a-trihydroxypregnan-ZO-one by the method ofPreparation 26.

In the same manner other21-aceyloxy-3fi,11a,17a-trihydroxypregnan-ZO-ones are prepared from2l-bromo- 35,11a,17wtrihydroxypregnan-20-one and the appropriatepotassium acylate, including 2l-formyloxy-3p,1leflet-trihydroxypregnan-ZO-one;21-pr0pi0I1OXY-3I3,11a,17a-trihydroxypregnan 20 one; 21 butyryloxy3fi,llcz,17rr trihydroXy regnan-ZO-One; 21-valeryloxy-3p,1 1a,17oc-t1ihydroxypregnan-ZO-one; hydroxypregnan-20-one; 2 1-heptanoy1oXy-35,1 1 on, 17 (It-trihydr Xyp egnfln-20-one; 21-octanoyloxy-3p,1 111,17ot-trihydroxypregnan-ZO-one; and the like.

PREPARATION 29.--21-AcET0xY-3p,1 15,17a-TRIHYDROXY- PREGNAN-ZO-ONEdroxypregnan-ZO-one; and the like.

PREPARATION 30.--1 1a,21-DIAcEToxY-3u, 17 ot-DIHYDROXY- PREGNAN-ZO-ONEUsing the method of Preparation 26, 11a,21-diacetoxy-3a,l7a-dihydroxypregnan-20-one is produced from 21- bromo 11a acetoxy3a,17ot dihyclroxypregnan 20- one (Preparation 23).

in the same manner other l1a,21-diacyloxy-3a,17otdihydroxypregnan-ZO-nesare prepared from the appropriate 21bromo-1 1ot-acyloxy-3 oz,l7cr-dihydroxypregnan- 20-one and the appropriate potassium acylate,including 21 acetoxy 1102 formyloxy 3a,l7oz-dihydroxypregnan- 20-one; 2l -propionoxy-1 1a-acetoxy-3 a, 1 7m-dihydroxypregnan-20-one;21-butyryloxy-11ot-acetoxy-3a,17wdihydroxypregnan-ZO-one 2 l-valeryloxy-I 1 ot-acetoxy-3 ot,17otdihydroxypregnan-ZO-one;21-hexanoyloxy-1lot-acetoxy- 3(1,17at-dihydroxypregnan-20one;21-heptanoyloxy-1 1aacetoxy-3a,17ot-dihydroxypregnan-20-one;21-octanoyloxy lla acetoxy 312,170: dihydroxypregnan 2O one; 1111,21dipropionoxy 3a,17wdihydroxypregnan-20-one; 110;,21 dibutyryloxy3a,17a-dihydroxypregnan-20-one; 11a,2ldihexanoyloxy-fw,17nt-dihydroxypregnan-20'one; 1111,21 dioctanoyloxy-3u,l7a-dihydroxypregnan-20-pne; 21 acetoxyl1ot-pr0pionoxy-3ot,17ot-dihydroxypregnan- 20-one; and the like.

PREPARATION 3 1.1 1a,21-DIAcnToxY-3 8,17ot-DInYDRoxY- PREGNAN-ZO-ONE 21bromo 11ct-acetoxy-3fi,17a-dihydroxypregnan-20- one (Preparation 24) istreated with potassium acetate according to the procedure of Preparation26 to give 11a,21-diacetoxy3[i',17wdihydroxypregnan-20-one in highyield.

In the same manner otherlla,2l-diacyloxy-3fl,17otdihydroxyprcgnan-20-ones are prepared from theappropriate 21-bromo-11ot-acyloxy-3/i,17a-dihydroxypregnan- 20-one andthe appropriate potassium acylate, including 21formyloxy-l1a-acetoxy-3fi,17ot-dihydroxypregnan-20- one; 21-propionoxy-1loz-EiClZOXY-3l3,17a-dihYflIOXY-Pregnan-20-one; 21-butyryloxy-11ot-acetoxy-35, l 7a-dihydroxypregnan-20-one; 2 1-valeryloxy-11u-acetoxy'35, 17a-dil1ydroxypregnan 20 one; 21hexanoyloxy-llat-acetoxy- 3p,17ot-dihydroxypregnan-20-one;21-heptanoyloxy-1 1w acetoxy-3,8,17ot-dihydroxypregnan-ZO-one; 2 l--octanoyloxy 11cc acetoxy 3fi,1766 dihydroxypregnan 20-one; 1101,21clipropionoxy 3e,l7ot-dihydroxypregnan-20-one; 1la,21 dibutyryloxy3/3,17ct-dihydroxypregnan-ZO-one; 11oc,2ldihexanoyloxy-3p,17a-dihydroxypregnan-20-one; 1111,21 dioctanoyloxy-35,17a-dihydroxypregnan-ZO-one; 21 acetoxy11a-propionoxy-35,17wdihydroxypregnan- 20-one; and the like.

The 21-acyloxysteroids obtained in Preparation 26 through Preparation 31from the 2l-bromosteroids may also be obtained in the same manner bysubstituting the corresponding 21-chlorosteroid (Preparation 25) for the2l-bromosteroid specified.

Example 1 .Pregnane-3,11,20-tri0ne To a stirred solution of 400milligrams (1.2 millimoles) of 3a-hydroxypregnane-l1,20-dione [Von Euw,Lardon and Reichstein, Hclv. Chim. Acta, 27, 821 (1944)] in eightmilliliters of anhydrous tertiary-butyl alcohol is added 0.5 milliliter(about 4.4 millimoles) of tertiarybutyl hypochlorite prepared accordingto the procedure of Chattaway and Backeberg, J. Chem. Soc., 125, 2999(1923). The reaction mixture is kept in the dark and stirred for fourhours at room temperature whereafter the Whole is evaporated to drynessat room temperature giving a quantitative yield of 400 milligrams ofpregnanc- 3,11,20-trione which, without purification, melts at 146 to151 degrees centigrade and has an infrared absorption spectrum identicalwith that of an authentic sample.

Example 2.17a-hydr0xy-21-acetoxypregnane-3,1 1,20- trione In the samemanner as described in Example 1, 0.50 gram (1.2 millimoles) of3a,l7a-dihydroxy-2l-acetoxypregnane-l1,20-dione [Sarett, I. Am. Chem.Soc, 70, 1454 (1948)] is reacted for five hours in the dark at roomtemperature with 0.4 milliliter (about 3.5 millimoles) of tertiary-butylhypochlorite in 25 milliliters of anhydrous tertiary-butyl alcohol,whereafter the whole is evaporated to dryness at reduced pressureleaving the theoretical yield of 0.50 gram of 17oc-hYd1'0XY-2l-HC61IOXY-pregnane-3,11,20-trione which, without purification, melts at 215 to 221degrees Centigrade and has an infrared absorption spectrum which isidentical with. that of an authentic sample. Bromination at the4-position followed by dehydrohalogenation yields cortisone acetate.

Example 3.-17m-hydr0xypregnane-3,11,20-trione In the same manner asdescribed in Example 1, 0.86 gram of 3a,17a-dihydroxypregnane41,20'dione[Sarett, J. Am. Chem. Soc, 70, 1454 (1948)] is reacted with 0.875 gramof tertiary-butyl hypochloriate in fifty milli liters of anhydroustertiary-butyl alcohol. The reaction mixture is stirred and kept in thedark at room temperature for two hours. The consumption of thetertiarybutyl hypochlorite is followed by periodical iodometrictitrations of aliquot samples, the theoretical amount of tertiary-butylhypochlorite being consumed in one hour Whereafter no more is consumed.Removal of the volatile components of the reaction mixture bydistillation at reduced pressure gives as the residue the theoreticalamount of 17a-hydroxypregnane-3,11,20-trione which, Withoutpurification, melts at 193 to 198 degrees centigrade and has an infraredspectrum analysis which is identical with that of an authentic sample.Bromination at the 4 and 2l-positions, followed by dehydrohalogenationto introduce a 4-double bond, and finally treatment with potassiumacetate to replace the 21-bromine atom with an acetoxy group, yieldscortisone acetate.

Example 4.Clz0lestan-3-0ne In the same manner as described in Example 1,0.39 gram of cholestan-Bfi-ol is reacted in the dark at room temperaturefor five hours with 0.4 milliliter of tertriarybutyl hypochlorite in 25milliliters of anhydrous tetriarybutyl alcohol whereafter the volatilecomponents of the reaction mixture are removed by distillation atreduced pressure leaving a quantitative yield of cholestan-3-one as theresidue which, without purification, melts at 126.5 to 128 degreescentigrade and has an infrared absorption spectrum which is identicalwith that of an authentic sample.

In the same manner as described above using the same quantities of thesame reactants but conducting the reaction in the presence of lightinstead of in the dark for a reaction period of three hours instead offive hours, and then pouring the reaction product into water andremoving the solid by filtration instead or" distilling the solvents toisolate the solid product, 0.35 gram oi: 2-chlorocholestan-3-one isobtained, melting point 1l5130 degrees centigrade.

Example 5.-Allopregnane-3,11,20-tri0ne In the same manner as describedin Example 1, 184 milligrams of 3fl-hydroxyallopregnane-l1,20-dione[Stork et al., J. Am. Chem Soc., 73, 3546 (1951)] dissolved in ninemilliliters of tertiary-butyl alcohol is reacted overnight at roomtemperature with 0.19 milliliter of tertiarybutyl hypochloritewhereafter 143 milligrams of allopregnane-3,11,20trione which melts at203 to 207 degrees Centigrade and has an infrared absorption spectrumidentical with an authentic sample, crystallizes from the reactionmixture and is removed by filtration. Evaporation of the filtrate todryness provides an additional forty milligrams of allopregnane3,11,20-trione.

Example 6.I7a-hya'r0xy 21 br0m0pregnane-3,1l,20- trione In the samemanner as given in Example 1, two grams of 3a.,17a-dihYdIOXY 21bromopregnane 11,20 dione [Kritchevsky et al., J. Am. Chem. Soc., 74,483 (1952)] is reacted for 1.5 hours at room temperature with twomilliliters of tertiary-butyl hypochlorite in milliliters of anhydroustertiary-butyl alcohol whereafter the volatile components are removed bydistillation at reduced pressure leaving as the residue the theoreticalquantity of 17a-hydroxy-2l-bromopregnane-3,11,20-trione which, withoutpurification, melts at 210 to 214 degrees centigrade. Recrystallizationof this material gives product melting at 220 to 225 degrees centigrade.Bromination gives the 4,2l-dibromo compound which can be converted tocortisone acetate as shown in example 3.

Example 7.] 1 a-hydroxypregnane-3,20-dione In the same manner asdescribed in Example 1, 3a,11adihydroxypregnan-ZO-one [Von Euw, Lardonand Reichs'tein, Helv. Chim. Acta, 27, 1287 (1944)] is reacted withtertiary-amyl hypochlorite in tertiary-amyl alcohol at 35 degreescentigrade to produce 11a-hydroxypregnane-3,20- dione, an analyticalsample of which melts at 126 to 127 degrees centigrade. 4-brominationfollowed by dehydrohalogenation yields the knownlla-hydroxyprogesterone.

Selective reduction of 11a-acetoxypregnane-3,20-dione (Preparation 12)with sodium borohydride in dioxane 7 and water is productive of3a-hydroxy-1lot-acetoxypregn'an-ZO-one melting at 122 to 136 degreescentigrad'e, which, in the same manner as described in Example 1, is'reacted with ethyl hypochlorite in a large volume of anhydroustertiary-amyl alcohol at about zero degrees centigrade for 24 hours toproduce lla-acetoxypregnane- 3,20-dion'e melting at 143.5 to 146.5degrees centigrade in high yield. Hydrolysis of the ester grouping gives11a.- hydroxypregnane-3,ZO-dione identical with the product obtainedabove.

Example 8.-21-chl0r0 17a hydroxypregnane-3,11,20- trione Treatment of3a,17a-dihydroxypregnane 11,20 dione ISarett, I. Am. Chem. Soc., 70,1454 (1948)] with chlorine in acetic acid is productive of3a,17a-dihydroxy-21-chloro pregnane-11,20-dione.

In the same manner as described in Example 1, reacting3a,17a-dihydroxy-2l-chloropregnane-11,20-dione with terl tiary-butylhypochlorite in tertiary-butyl alcohol is productive of2l-chloro-17a-hydroxypregnane-3,11,20-trione in high yield.

21-chloro-17a-hydroxypregnane-3,11,20-trione is brominated in the4-position with bromine in acetic acid, dehydrohalogenated to produce a4(5)-double bond using semicarbazide hydrochloride followed by pyruvicacid, and then treated with potassium acetate to obtain cortisoneacetate.

Example 9.-] 7 a-hydroxypregnane-3 ,1 1 ,ZO-trione In the same manner asdescribed in Example 3, a solution of311,11,8,17a-trihydroxypregnan-ZO-one (Preparation 2) in anhydroustertiary-butyl alcohol is reacted with tertiary-butyl hypochlorite togive a high yield of 17ahydroxypregnane-3,l1,20-trione, melting at194-198 degrees centigrade and identical with the product of Example 3.

In the same manner as shown above, 35,115,17a-t'rihydroxy pregnan-20-one(Preparation 8) is converted to 17a-hydroxypregnane-3 ,1 1,20-trione.

Example 10.11a,17a-dihydr0xypregnane-3,20-d0ne Example -11.1Ia-acet0xy17a hydroxypregnane-SJO- dione 11a-acetoxy-3a,17a-dihydroxypregnan 20one (Preparation 17) is transformed, according to the method of Example1, into l1a-acetoxy-17a-hydroxypregnane-3,20- dione, the yield beingabout the theoretical amount. In the same manner11a-acetoxy-3p,17a-dihydroxypregnan- 20-0ne (Preparation 18) gives11a-acetoxy-17a-hydroxypregnane-3,20-dione.

In the same manner other 1la-acyloxy-17a-hydroxypregnane-3,20-diones areprepared from 11a-acy1oxy-3a(or B),17a-dihydroxypregnan-ZO-ones,including 11a-formyl oxy-17a-hydroxypregnane 3,20 dione; 11apropionoxyl7a-hydroxypregnane-3,20-dione;lla-butyryloxy-lh-hydroxypregnane-3,20-dione; lla-valeryloxy 17a.hydroxypregnane-3,20-dione;1la-hexanoyloxy-17a-hydroxypregnane-3,20-dione;11a-heptanoyloxy-17a-hydroxypregnane- 3,20 dione;1la-octanoyloxy-17a-hydroxypregnane-3,20- dione; and the like.

The 11a-acyloxy-17a-hydroxypregnane-3,20-diones may be converted tocortisone acetate by brominating at the 4 and 21-positions using brominein acetic acid to produce the 4,2l-dibromo-1la-acyloxy-17a-hpdroxypregnane-3 ,20- diones, dehydrohalogenating withpyridine to remove hydrogen bromide and obtain 21-bromo-11a-acyloxy-17a.1

hydroxy-4-pregnene 3,20 diones, hydrolyzing the 21- bromine and thella-acyloxy group to produce 1la,17u.,21-trihydroxy-4-pregnene-3,20-dione using sodium hydroxide in aqueousalcohol, acetylating the 21-hydroxyl group with one equivalent of aceticanhydride in pyridine to produce 21-acetoxy-11a,17a-dihydroxy-4-pregnene-3 ,20-dione, and mildly oxidizing theIla-hydroxy group with chromic acid in acetic acid to produce aneleven-keto group.

Example 12.21 bromo 11a,,17a dihydroxypregnane- 3,20-di0ne Following themethod of Examples 6, 21-bromo-3a,- 11a,17a-trihydroxypregnan-20-one(Preparation 19) gives 21-bromo-11a,17a-dihydroxypregnane 3,20 dione inexcellent yield. In the same manner21-bromo-11a,17a-dihydroxypregnane-3,20-dione is obtained from 21-bromo-3,8,11m,17a-trihydroxypregnan-20-one (Preparation 21).

Mild oxidation of the lla-hydroxy group of 21-bromo-11a,l7a-dihydroxypregnane-3,20-dione gives 21-bromo-17a-hydroxypregnane-3J1,20-trione which can be converted to cortisoneacetate as shown in Example 6.

Example 13.-21-br0m0-17a-hydr0xypregnane- 3,11,20-tri0ne According tothe procedure of Example 1, 21-bromo-311,1lf3,17a-trihydroxypregnan-2O-one (Preparation 20) is converted to21-bromo-17a-hydroxypregnane-3,11,20-trione, which is identical with theproduct of Example 6 in essentially quantitative yield; melting point215220 degrees centigrade. In the same manner 21-bromo- 3B,l1f,17a-trihydroxypregnan-20-one (Preparation 22) yields 21 bromo 17ahydroxypregnane 3,11,20 trione which may be converted to cortisoneacetate as shown in Example 6.

Example 14.21-br0m0-11 a-acetoxy-l 7a-hydroxypregnane-iZO-dione 21 bromo11oz acetoxy 3a,l7ot dihydroxypregnan 20-one is treated withtertiary-butyl hypochlorite accord- '1 ing to the method of Example 3 toobtain 21-bromodione; 21 brozno 11a butyryloxy 170a hydroxypregnane 3,20dione; 21 brorno 11cc valeryloxy 17o: hydroxypregnane 3,20 dione; 21bromo 11a hexanoyloxy 17a hydroxypregnane 3,20 dione; 21 bromo 11aheptanoyloxy 17a hydroxypregnane 3,20 dione; 21 brorno 110, octanoyloxy17oz hydroxypregnane-3,20-dione; and the like.

21 bromo 11a acyloxy 170: hydroxypregnane 3,20-diones may be convertedto cortisone acetate as shown in Example 11.

Example .75.-2] chZo-ro 11:1,I7oc dihyclroxypregnane 3,20-(Hone 21chloro 3a,llot,l7ot trihydroxypregnan one (Preparation is converted,according to the method of Example 1, to 21-chloro1]IM-dihydroxypregnane- 3,20-Cliche In the same manner other21-chloro-1l-oxygenated-lhhydroxypregnane-3,20-diones are prepared fromcorresponding 21 chloro 11 oxygenated 3,17cx dihydroxypregnan 20 ones,including 21 chloro lloc propionoxy 17a: hydroxypregnane 3,20 dione; 21chloro 11a. formyloxy 17oz hydroxypregnane 3,20 dione; 21 chloro 111xbutyryloxy 17o: hydroxypregnane 3,20 dione; 21 chloro 11a. valeryloxy17oz hydroxypregnane 3,20 dione; 21 chloro 110: hexanoyloxy 17cchydroxypregnane 3,20 dione; 21 chloro lie: heptanoyloxy 17ahydroxypregnane 3,20 dione; 21 chloro 11a octanoyloxy 17a.hydroxypregnane-3,20-dione; and the like.

The 2l-chloro derivatives may be converted to cortisone acetate in thesame manner as the 21-oromo derivatives of Example 12 through Example14.

Example lei-2] acetoxy 1106,1705 dihydroxypregnane-3,20-di0=ne Using themethod of Example 1, 2l-&ClZOXy-3u,11a,17ottrihydroxypregnan-20-one(Ereparation 26) gives about the theoretical amount of21-acetoxy-1lot,17a-dihydroxypregnane-3,20-dione. In the same manner21-acetoxy- 3B,l1a,170: trihydroxypregnan 20 one (Preparation 28) isconverted to 2i-acetoxy-11e,17a-dihydroxypregnane-3,20-dione.

Other 21 acyloxy llot,17oc dihydroxypregnane 3,20-dimes are preparedfrom the appropriate 21-acyloxy- 3u(or [3),11t1,17e trihydroxypregnan 20ones in the same manner, including21-propionoxy-11a,17u-dihydroxypregnane 3,20 dione; 21 formyloxy1141,17; dihydroxypregnane 3,20 dione; 21 butyryloxy 110:,17rxdihydroxypregnane 3,20 dione; 21 valeryloxy l1rx,l70t dihydroxypregnane3,20 dione; 21 hexanoyloxy 110:,l7a dihydroxypregnane 3,20 dione; 21heptanoyloxy 1101,1704 dihydroxypregnane 3,20 dione; 21 octanoyloxyllcc,17a dihydroxypregnane-3,20-dione; and the like.

21 acyloxy 11e,17a dihydroxypregnane 3,20 diones are oxidized withchromic acid in acetic acid under mild conditions to obtain2l-acyloxy-l7a-hydroxypregnane-3,11,20-triones which are convertible tocortisone acylates as shown in Example 2 for cortisone acetatepreparation.

Example I 7.2J -acetoxy-l7a-hydr0xypregnane- 3,11,20-tri0ne 21 acetoxy30,1 13,170; trihydroxypregnan 20 one (Preparation 27) is treated withabout six molar equivalents of tertiary-butyl hypochlorite according tothe method of Example 2 to give nearly the theoretical quantity of21-acetoxy-17a-hydroxpregnane-3J1,20-trione melting at 216221 degreescentigrade, identical with the product of Example 2. The same product isobtained in the same manner starting with2]-acetoxy3;3,11fi,17e-trihydroxypregnan-20-one.

In the same manner other 21-acyloxy l7a-hydroxypregnane-3,11,20-trionesare prepared from corresponding 21-acy1oxy-3a( or [3),11,8,1711-1rihydroxypregnan-20- chlorite, hexyl hypochlorite,

ones, including 21 propioncery 17a hydroxypregnane 3,11,20 trione; 21forrnyloxy 17a hydroxypregnane 3,11,20 trione; 21 butyryloxy 17ahydroxypregnane 3,11,20 trione; 21 valeryioxy 17o: hydroxypregnane3,11,20 trione; 21 hexan-oyloxy 1704 hydroxpregnane 3,11,20 trione; 21heptanoyloxy 17o: hydroxypregnane 3,11,20 trione; 21 octanoyloxy 17ahydroxypregnane 3,11,20 trione; and the like.

21 acyloxy 170C hydroxypregnane 3,11,20 triones are convertible tocortisone acylates as shown in Example 2 for cortisone acetatepreparation.

Treating 11u,2l diacetoxy 30,17a dihydroxypregnan-20-one (Preparation30) with tertiary-butyl hypochlorite according to the procedure ofExample 1 gives high yields of 11a,21-diacetoxy-17ot-hydroxypregnane-3,20-dione; melting point 222 to 226 degrees centigrade. 1n the samemanner 11a,21-diacetoxy-3/3,17 x-dihydroxypregnan-ZO-one (Preparation31) is converted to 11a,21- diacetoxy 17a hydroxypregnane 3,20 dione insimilar yield.

Other 11,21 diacetoxy 17e-hydroxypregnane-3,20- diones are prepared from1111,21 -diacyloxy-3a(or [3),1711- dillydroxypregnamZO-ones in the samemanner, includ ing 1111'. acetoxy-Zl-propionoxy-lia-hydroxypregnane-3,20 dione; 11a acetoxy-Zl-forrnyloxy-l.7a-hydroxypregnane-3,20-dione;1le-acetoxy-21-hutyryloxy-17u-hyroxypregnane-3,20-dione; 1 1a-aeetoxy-21 -va1ery1oxy-17ahydroxypregnane-3,ZO-dione; 11a-aeetoxy-21-hexanoyloxy17a hydroxypregnane-3,ZO-dione; 11a-acetoxy-21- hep'tanoyloxy 17ahydroxypregnane 3,20 dione; 11- acetoxy 21 octanoyloxy 17a hydroxypregnane 3,20 dione; 1104,21 dipropionoxy 17a hydroxypregnane3,20-dione; 1111,21-diformyloxy-l7a-hydroxypregnane-3,20-dione; 11e,21dihutyryloxy-l7a-hydroxypregnane 3,20 dione; 11:4,21dihexanoyloxy-lh-hydroxypregnane 3,20-dione;11a,21-dioctanoyloxy-17ahydroxypregnane-3,20-dione; 11e-propi0noxy2l-acetoxy- 17ot-hydroxypregnane-3,20-dione; and the like.

4-hromination of the 11e,21-diacy1oxy-17a-hydroxypregnane-3,20-dionesand treatment of the 4-bromo- 11a,2ldiacyloxy-l7a-hydroxypregnane-3,20-diones with semicarbazidehydrochloride followed by pyruvic acid gives 11a,21 diacyloxy17e-hydroxy-4-pregnene-3,20- diones. Saponification of thesediacyloxypregnenes with sodium hydroxide in aqueous alcohol gives11a,17a,21- trihydroxy-4-pregnene-3,ZO-dione which may he converted tocortisone acetate as shown in Example 11.

in the same manner as described in Example 1 through Example 18, othersecondary-hydroxysteroids are converted to ketosteroids usingtertiary-butyl, tertiary-amyl, or other hypochlorite, such as, forexample, propyl hypooctyl hypochlorite, or the like, including thefollowing examples: coprostanol or epicoprostanol gives coprostanone;304(01 ,8)-hydroxy-21- acetoxypregnane-l1,20-dione or 30(O1 [3),116-dihydroxy- ZI-acetoxypregnan-Zdone gives 21-acetoxypregnane-3,-11,20-trione, melting point to 158 degrees Centigrade, which on4-brornination followed by dehydrohalogenation yields the known21-acetoxy-4-pregnene-3,11,20- trione; 3a(or,6)-hydroxy-17-isoetiocholanic acid methyl r ester gives3-keto-17-isotiocholanic acid methyl ester;

3u,(01 5),11B-dihydroxypregnan-ZG-one gives pregnane-3, 11,20-trione;ll/i-hydroxycholanic acid methyl ester gives ll-ketocholanic acid methylester, 3a(or 3)-hydroxyallopregnan 20 one gives allopregnane 3,20 dionemeltir point 197 to 199 degrees centigrade; and other like examples.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art and 19 the invention is therefore to be limited only by thescope of the appended claims.

We claim:

1. A process which comprises: contacting a saturatedsecondary-hydroxy-steroid with an organic hypochlorite undersubstantially anhydrous conditions to convert the secondary-hydroxygroup to a keto group. 4

2. A process which comprises: contacting a saturatedsecondary-hydroxy-steroid with an alkyl hypochlorite under substantiallyanhydrous conditions in the presence of an organic solvent at atemperature between about minus twenty and about plus fifty degreescentigrade to convert the secondary-hydroxy group to a keto group.

3. A process which comprises: contacting a saturated 3-hydroxysteroidwith an organic hypochlorite under substantially anhydrous conditions toproduce a 3-ltetosteroid.

4. A process for the oxidation of a secondary-hydroxysteroid to alretosteroid which comprises: contacting a saturated 3-hydroxysteroidwith an alkyl hypochlorite under substantially anhydrous conditions inthe presence of an organic solvent at a temperature between about minustwenty and about plus fifty degrees Centigrade to produce a 3-ketosteroid.

5. A process for the oxidation of a secondary-hydroxysteroid to axetosteroid which comprises: contacting a saturated 3-hydroxysteroidcontaining no primary hydroxy groups with an alkyl hypochlorite undersubstantially anhydrous conditions in the presence of an organic solventat a temperature between about minus twenty and about plus fifty degreescentigrade to produce a 3- ketosteroid.

6. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a saturated1l-keto-ll-hydroxysteroid containing no primary or othersecondary-hydroxy groups with an alkyl hypochlorite containing more thanone carbon atom under substantially anhydrous conditions in the presenceof an Organic solvent at a temperature between about minus twenty andabout plus fifty degrees centigrade, to produce a 3,ll-diketosteroid.

7. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a saturated3,11a-dihydroxysteroid containing no primary or other secondary-hydroxygroups with an alkyl hypochlorite containing more than one carbon atomunder substantially anhydrous conditions in the presence of an organicsolvent at a temperature between about minus twenty and about plus fiftydegrees centigrade, to convert the 3-nydroxy group to a 3-keto group.

8. A process for the oxidation of a secondary-hydrox'y steroid to aketosteroid which comprises: containing a saturated3,llB-dihydroxysteroid containing no primary or other secondary-hydroxygroups with an alkyl hypochlorite containing more than one carbon atomunder substantially anhydrous conditions in the presence of an organicsolvent at a temperature between about minus twenty and about plus fiftydegrees Centigrade, to corivert the 3-hydroxy group to a S-keto group.

9. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a saturatedll-keto-3-hydroxysteroid containing no primary or othersecondary-hydroxy groups with at least about two molar equivalents of atertiary-alkyl hypochlorite under substantially anhydrous conditions inthe presence of an organic solvent at a temperature between about minustwenty and about plus fifty degrees centigrade to produce a3,11-diketosteroid.

10. A process for the oxidation of a secondary-hydroxysteroid to altetosteroid which comprises: contacting a saturated3,llo.-dihydroxysteroid containing no primary or other secondary-hydroxygroups with at least about two molar equivalents of a tertiary-alkylhypochlorite under substantially anhydrous conditions in the presence ofan organic solvent at a temperature between about minus twenty and aboutplus fifty degrees centigrade to produce a 3-keto-llot-hydroxysteroid.

11. A process for the oxidation of a secondary-hydroxysteroid to aketosteroi'd which comprises: contacting a saturated3,ll;B-dihydroxysteroid containing no primary or other secondary-hydroxygroups with at least about four molar equivalents of a tertiary-alkyl'hypochlorite under substantially anhydrous conditions in the presence ofan organic solvent at a temperature between about minus twenty and aboutplus fifty degrees centigrade to produce a 3,1l-diltetosteroid.

12. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting3,l7a-dihydroxy-pregnane-1l,20-dione with between about three and aboutfour molar equivalents of tertiary-butyl. hypochlorite undersubstantially anhydrous conditions in the presence of an organic solventat a temperature between about twenty and about thirty degreescentigrade to convert the 3-hydroxy group to a 3-keto group.

13. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting3,l7u-dihydrQXy-Zl-bromopregnane-l1,20-dione with between about threeand about four molar equivalents of tertiary-butyl hypochlorite undersubstantially anhydrous conditions in the presence of an organic solventat a temperature between about twenty and about thirty degreescentigrade to convert the 3-hydroxy group to a 3-keto group.

14. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a3,17a-dihydroxy-2l-acyloxypregnane-l1,20-dione with at least about twomolar equivalents of tertiarybutyl hypochlorite under substantiallyanhydrous conditions in the presence of an organic solvent at atemperature between about twenty and about thirty degrees centigrade toconvert the 3-hydroxy group to a 3-keto group.

15. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a3,11a,l7a-trihydroxy-2l-acyloxypregnan-ZO-one with at least about twomolar equivalents of tertiary-butyl hypochlorite under substantiallyanhydrous conditions in the presence of an organic solvent at atemperature between about twenty and about thirty degrees centigrade tocon-. vert the 3-hydroxy' group to a 3-keto group.

16. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a3,115,l7ot-trihydroxy-2l-acyloxypregnan-ZO-one with at least about fourmolar equivalents of tertiary-butyl hypochlorite under substantiallyanhydrous conditions in the presence of an organic solvent at atemperature between about twenty and about thirty degrees centigrade toconvert the 3-hydroxy group to a keto group.

17. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting3,17wdihydroxy-2l-acetoxypregnane-l 1,20-dione with between about threeand about four molar equivalents of tertiary-butyl hypochlorite undersubstantially anhydrous conditions in the presence of tertiary-butylalcohol at a temperature between about twenty and about thirty degreescentigrade to convert the 3-hydroxy group to a 3- keto group.

18. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting3,1la,l7u-trihydroxy-2l-acetoxypregnan-ZO-one with between about threeand about four molar equivalents of tertiary-butyl hypochlorite undersubstantially anhydrous conditions in the presence of tertiary-butylalcohol at a temperature between about twenty and about thirty degreescentigrade to convert the 3-hydroxy group to a 3- keto group.

19. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting3,11,8,l7a-trihydroxy-2l-acetoxypregnan-ZO-one with between about sixand about eight molar equivalents of tertiary-butyl hypochlorite undersubstantially anhydrous conditions in the presence of tertiary-butylalcohol at a temperature between about twenty and about thirty degreescentigrade to convert the 3-hydroxy group to a keto group.

20. A process for the oxidation of a secondary-hydroxysteroid to aketosteroid which comprises: contacting a S-hydroxysteroid of thefollowing formula:

22 wherein R is selected from the group consisting of a-hy droxy andfl-hydroxy; R1 is selected from the group consisting of hydrogen,a-hydroxy, a-acyloxy, .fi-hydroxy, and ketonic oxygen; R2 is selectedfrom the group consisting of hydrogen and hydroxy; and R3 is selectedfrom the group consisting of acetyl, bromoacetyl, chloroacetyl, andacyloxyacetyl; with at least about two molar equivalents of atertiary-alky1 hypochlorite under substantially anhydrous conditions inthe presence of an organic solvent at a temperature between about minustwenty and about plus fifty degrees centigrade to convert the 3-hydroxygroup to a 3-keto group.

References Cited in the file of this patent UNITED STATES PATENTS2,403,683 Reichstein July 9, 1946

1. A PROCESS WHICH COMPRISES: CONTACTING A SATURATEDSECONDARY-HYDROXY-STEROID WITH AN ORGANIC HYPOCHLORITE UNDERSUBSTANTIALLY ANHYDROUS CONDITIONS TO CONVERT THE SECONDARY-HYDROXYGROUP TO A KETO GROUP